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Treatment for benzodiazepine dependence & tolerance
In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low dose, slow infusion of flumazenil. One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with doctors being one of their most common patients.

Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg flumazenil. Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7–8 days of treatment with flumazenil.

Flumazenil has been tested against placebo in dependent subjects, whereby typical benzodiazepine effects were reversed with little to no withdrawal symptoms. Flumazenil was shown to produce significantly less withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine dependent subjects. Additionally, relapse rates were much less during subsequent follow-up.

Several studies have shown enhancement of the benzodiazepine binding site after chronic treatment with flumazenil where sites have become more numerous and uncoupling/down-regulation of GABAA has been reversed. After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
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